A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouse

• DOI: 10.1073/pnas.0709846104
• Publication Date: 2007-11-29T01:45:29Z
• Authors: Christian Grimm; Math P. Cuajungco; Alexander F. J. v...; Michael Schnee; Simone Jörs; Corné J. Kros; Anthony J. Ricci; Stefan Heller
• Keywords: 0301 basic medicine; Proline; Molecular Sequence Data; TRPM Cation Channels; Apoptosis; Protein Structure, Secondary; Cell Line; Protein Structure, Tertiary; Mice; 03 medical and health sciences; Transient Receptor Potential Channels; Amino Acid Substitution; Animals; Amino Acid Sequence; Hearing Loss

Homozygote varitint-waddler (Va) mice, expressing a mutant isoform (A419P) of TRPML3 (mucolipin 3), are profoundly deaf and display vestibular pigmentation deficiencies, sterility, perinatal lethality. Here we show that the carrying an A419P mutation represents constitutively active cation channel can also be identified in native hair cells as distinct inwardly rectifying current. We hypothesize constitutive activation occurs result helix-breaking proline substitution transmembrane-spanning domain 5 (TM5). A scan demonstrated inner third TRPML3's TM5 is highly susceptible to proline-based kinks. Proline substitutions other TRP channels revealed TRPML1, TRPML2, TRPV5, TRPV6 similar susceptibility at comparable positions, whereas were not affected. conclude molecular basis for deafness mouse cell death caused by activity. To our knowledge, study provides first direct mechanistic link ion with mammalian hearing loss.